1. Field of the Invention
The present invention pertains to topical compositions which aid in the healing of wounds.
2. Description of the Related Art
While some of the lower vertebrates are able to regenerate tissue without scarring, e.g. salamanders, with the exception of repair of the endometrium, wounds to human tissue, and particularly skin, are always accompanied by the production of scar tissue.
Wounds may be produced in numerous ways, by burns, punctures, abrasion or tearing of the skin, and by surgery. The mechanism of wound healing has been intensively studied, and is very complex. Some studies have classically divided the healing process into four considerably overlapping phases: hemostasis, inflammation, proliferation, and remodeling. More recently, a division into only two major phases, the early phase and the later phase, has been proposed. “4. The Pathophysiologic Basis For Wound Healing and Cutaneous Regeneration,” BIOMATERIALS FOR TREATING SKIN LOSS, Elsevier, Jan. 28, 2009, pp. 25 ff.
Regardless of the theoretical construct used to describe the healing process, all models agree that there is an initial phase involving a clotting cascade, forming a mass of blood platelets aggregated by sticky glycoproteins. Fibrin and fibronectin crosslink to form a plug which traps proteins and particles, and prevents further blood loss. This plug forms the initial main structural support for the wound prior to deposition of collagen. K. S. Midwood, et al., “Tissue Repair and the Dynamics of the Extracellular Matrix,” INT'L. J. BIOCHEMISTRY AND CELL BIOLOGY, 36 (6) 1031-1037. This plug is eventually lysed and replaced with granulation tissue.
At a later stage aniogenis (neovascularization) begins, accompanied by fibroblast-initiated formulation of granulation tissue and collagen deposition. The collagen is important in holding the wound closed, since the tensile strength of the fibrin-fibronectin clot is only marginal. Near the end of granulation, remaining fibroblasts commit apoptosis, converting granulation tissue from one rich in cells to one consisting principally of collagen. W. K. Stadelmann et al., “Physiology and Healing Dynamics of Chronic Cutaneous Wound,” AM. J. SURGERY, 176 (2 A. Suppl.): 265-385 (1998). This process forms the scaffold upon which reepithelialization takes place. Basal keratinocytes from the wound edges form epithelial cells which migrate in a sheet across the wound site. The more quickly these cells proliferate and migrate, the less scar formation is observed. H. J. Son, et al., “Effects of β-glucan on Proliferation and Migration of Fibroblasts,” CURRENT APPLIED PHYSICS, 5 (5) 468-71 (2005).
Scarring is a natural part of the healing process. Scar tissue differs from normal tissues in several ways. For example, sweat glands and hair follicles are exceptionally deficient or totally absent. Moreover, while scar tissue is composed of collagen protein just like normal tissue, the collagen fibers of scar tissue crosslink during fibrosis to form a structure with pronounced alignment of fibers, whereas in normal tissue, a basketweave of collagen fibers is present. J. A. Sheralt, “Mathematical Modeling of Scar Tissue Formation,” Department of Mathematics, Heriot-Walt University (2010).
A conclusion which can be reached, is that scar formation can be minimized by rapid reepithelization. However, for this to occur, conditions must be established which promote the proliferation of epithelial cells and their migration. One proposed solution to this problem is to cover the wound with a hydrophobic substance with little water permeability. Silicone gels, silicone sheets, and oleaginous substances such as mineral oils and petrolatum-based ointments have been proposed for this purpose. However, the effect of such products is less than desired. One study found that there was no significant improvement in patients not at high risk for scarring. M. H. Gold, “Prevention of Hypertrophic Scars and Keloids by Prophylactic Use of Topical Silicone Gel Sheets Following a Surgical Procedure in an Office Setting,” DERMATOL. SURG. 27: 641, (2001).
The problem with an occlusive approach to increase reepithelization is that while escape of the moisture present in the wound is decreased, the dressings do not allow external moisture to enter the wound, and that there is no mechanism for increasing the moisture content of the wound from the body tissue and blood vessels, i.e. from within. Nor do such treatments favor the production of the myriad of growth factors which are involved in wound healing.
A variety of herbal and alternative medicines have been proposed, including the use of extract from the bark of Spathodea campanulata beauv, titrated extracts of Cemtelia asratica, Anogeissus latifola bark extract, and Channa striatus fish extract combined with cetrimide cream, but no clinical trials had been reported. Topical onion skin extract (Mederma™, Merz Pharmaceuticals) proposes to reduce scarring, but has not been shown to produce any improvement as compared to petrolatum emollient. R. Shih, M. D., et al. “Review of Over-The-Counter Topical Scar Treatment Products,” PLASTIC AND RECONSTRUCTIVE SURGERY 119 (3): 1091-5 © 2007.
It would be desirable to provide a topical composition which exhibits moisture retention, encourages production of additional moisture in situ, and also encourages the proliferation and migration of epithelial cells.
Eczema, sometimes called “dermatitis,” is a little understood skin inflammation characterized by itchy, erythematous, vesicular, weeping, and crusty patches. Eczema may be triggered by allergic reactions to specific allergens. However, it is believed to be at least partially genetic, and recent studies have identified several genetic variants associated therewith. L. Paternoster, et al., “Meta-analysis of Genome-wide Association Studies Identified Three New Risk Loci For Atopic Dermatitis,” NATURE GENETICS 44 (2) pp. 187-82, (2011). Treatment generally involves topical corticosteroids or topical immunosuppressants. However, long term use of such compositions is problematic. Ultraviolet light therapy has also been recommended, but extensive treatment may be expected to increase the risk of skin cancer.
Psoriasis is another not well understood skin disease, characterized by patches of abnormal skin. The most common form is plaque psoriasis, symptoms of which include raised areas of inflamed skin covered with scaly white or silvery skin. Psoriasis is also thought to have a genetic causation factor, and is considered to be an autoimmune disease. “Questions and Answers about Psoriasis,” NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKI DISEASES, October 2013. No cure is known to exist, but symptoms can be lessened with topical corticosteroids, vitamin D analogs, and especially combinations of these. Moisturizers and emollients such as mineral oil and petrolatum have been found to increase clearance of plaques, especially in conjunction with phototherapy. Curiously, daily baths in the Dead Sea for an extended period (4 weeks) with sun exposure have shown 75% decreased symptoms and remission for several months. Unfortunately, such treatment is not available to most. Systemic treatments are available and being strongly pursued, but most require regular blood and liver function tests to assess toxicity.
It would be desirable to provide a topical composition with little or no toxicity, which can be tolerated for long periods of time, and which reduces the symptoms of eczema and psoriasis.